Bis-thioureido-benzenes and preparation thereof

ABSTRACT

THE COMPOUNDS HAVING EITHER FORMULA   R-Y-CO-NH-C(=S)-N(-R2)-(XN-1,2-PHENYLENE)-N(-R3)-C(=S)-   NH-CO-Y-R1, OR R-Y-C(-O(-))-N-C(-S(-))-N(-R2)-(XN-1,2-   PHENYLENE)-N(-R3)-C(-S(-))-N-C(-O(-))-Y-R1 M(+4) WHERE   BOTH O&#39;&#39;S AND S&#39;&#39;S ARE ATTACHED TO M   (WHEREIN EACH OF R AND R1 REPRESENTS ALKYL OF 1 TO 12 CARBON ATOMS, ALKYL OF 1 TO 2 CARBON ATOMS SUBSTITUTED WITH HALOGEN, METHOXY OR PHENYL, ALKENYL HAVING 2 TO 3 CARBON ATOMS, ALKNYL HAVING 2 TO 3 CARBON ATOMS, ARYL OR ARYL SUBSTITUTED WITH HALOGEN, NITRO OR METHYL; EACH OF R2 AND R3 REPRESENTS HYDROGEN OR METHYL; X REPRESENTS HALOGEN, NITRO OR METHYL; N REPRESENTS INTEGER OF 0-3; Y REPRESENTS OXYGEN OR SULFUR AND M REPRESENTS METAL) ARE PREPARED IN ACCORDANCE WITH THE FOLLOWING EQUATIONS:   1-(R2-NH-),2-(R3-NH-),XN-BENZENE AND 2(SCN-CO-Y-R) -&gt;   R-Y-CO-NH-C(=S)-N(-R2)-(XN-1,2-PHENYLENE)-N(-R3)-C(=S)-   NH-CO-Y-R1 AND 2(M&#39;&#39;-OH) -&gt; R-Y-CO-N(-M&#39;&#39;)-C(=S)-   N(-R2)-(XN-1,2-PHENYLENE)-N(-R3)-C(=S)-N(-M&#39;&#39;)-CO-Y-R1 AND   M(+2) -&gt; R-Y-C(-O(-))-N-C(-S(-))-N(-R2)-(XN-1,2-PHENYL-   ENE)-N(-R3)-C(-S(-))-N-C(-O(-))-Y-R1 M(+4) WHERE   BOTH O&#39;&#39;S AND S&#39;&#39;S ARE ATTACHED TO M   WHEREIN M&#39;&#39; REPRESENTS ALKALI METAL ATOM AND THE NOVEL COMPOUNDS HAVE BROAD FUNGICIDAL ACTIVITY WITH VERY LOW MAMMALIAN TOXICITY.

United States Patent Office 3,745,187 BIS-THIOUREIDD-BENZENES AND PREPARATION THEREOF Teruhisa Noguchi, Keisuke Kohmoto, Yasushi Yasuda, and Sho Hashimoto, Kanagawa, Kinpei Kato, Tokyo, and Koshin Miyazaki and Daigaku Takiguchi, Toyama, Japan, assignors to Nippon Soda Company, Ltd.,

Tokyo, Japan No Drawing. Original application Oct. 28, 1968-, Ser. No.

771,269. Divided and this application Oct. 21, 1971,

Ser. No. 191,496

Claims priority, application Japan, Oct. 30, 1967, 42/69,:358; Dec. 27, 1967, 43/815,295; Apr. 13, 1968, 43/24,528; Apr. 19, 1968, 43/25,829; June 18, 1968, 43/41,587, LS/41,589

Int. Cl. C07c 125/00, 155/02 (wherein each of R and R represents alkyl of 1 to 12 carbon atoms, alkyl of 1 to 2 carbon atoms substituted with halogen, methoxy or phenyl, alkenyl having 2 to 3 carbon atoms, alkynyl having 2 to 3 carbon atoms, aryl or aryl substituted with halogen, nitro or methyl; each of R and R represents hydrogen or methyl; X represents halogen, nitro or methyl; n represents integer of -3; Y represents oxygen or sulfur and M represents metal) are prepared in accordance with the following equations:

wherein M' represents alkali metal atom and the novel compounds have broad fungicidal activity with very low mammalian toxicity.

This application is a division of United States patent application Ser. No. 771,269, filed Oct. 2-8, 1968.

This invention relates to novel bis-thioureidobenzenes having superior fungicidal activity and to a process for the preparation of the same. Further, the invention relates to fungicidal compositions containing one or more of said novel compounds and further includes methods for combatting fungi with the same compounds.

The-novel compounds in the present invention are characterized by one of the following formulas:

I (wherein each of R and R represents a monovalent radical selected from the group consisting of alkyl of 1 to 12 carbon atoms; alkyl of 1 to 2 carbon atoms substituted with halogen, methoxy or phenyl; alkenyl having 2 to 3 carbon atoms; alkynyl having 2 to 3 carbon atoms; aryl or aryl substituted with halogen, nitro or methyl; each of R and R represents hydrogen or methyl; X represents halogen, nitro or methyl; n represents an integer from 0 to 3; Y represents oxygen or sulfur and M represents a metal atom.) 'The compounds have superior fungicidal activity against various plant diseases such as rice blast disease, cucumber anthracnose. Cercospora leaf spot of sugar beets and rice sheath blight disease. It is an advantage of the invention that said compounds have very low mammalian toxicity.

The compounds of this invention can be prepared by the reactions illustrated below, wherein R, R R R, X, Y and n are defined as above:

3,745,187 Patented July 10,, 1973- The reaction Equation 1 is carried out in an inert organic solvent such as acetone, methylethylketone, methanol, ethanol, dioxane, acetonitrile, benzene or toluene, at a temperature of -150" C., preferably, 60 C., ordinarily in about ten minutes to one hour, but occasionally in several hours. After the reaction ends, the compound is isolated from the reaction mixture by conventional techniques. For example, the reaction mixture may be cooled or added to water. The precipitated material is separated from the solution by filtration. Instead, solvent may be distilled ofi from the reaction mixture. If necessary, the prepared compound may be further purified by washing with water and by recrystallizing from a solvent such as acetone, methanol, ethanol and dioxane.

The reaction Equation 2 is carried out smoothly in aqueous solution at normal room temperature. After the reaction, precipitated material is separated from the solution by conventional procedures, such as filtration. The desired product may be obtained by washing the precip itate with water and hot acetone. The reaction Equation 2 is preferably carried out when the sulfate or the chloride of Cu, Ca or Ba is used to supply M++.

In order to facilitate a clear understanding of the invention, the following preferred specific embodiments are described as illustrative and not as limiting the invention.

EXAMPLE 1 1,2-bis- 3-ethoxycarbonyl-2-thioureido benzene (Compound 2) 59.0 g. (0.54 mol.) of ethyl chloroformate were added to 54.4 g. (0.56 mol.) of potassium thiocyanate in 300 ml. of acetone at room temperature under agitation, and the mixture was heated and kept at a room temperature of 35-45 C. on a water bath [for one hour. Then the mixture containing the resulting ethoxycarbonylisothiocyanate was cooled and kept at a temperature of 10-20 C. on an ice water bath under agitation. 15.5 g. (0.143 mol.) of o-phenylenediamine were dropped into the mixture, while it was maintained at a temperature of l0-20 C. on an ice water bath under agitation. Then the reaction mixture was kept at room temperature for one hour, and allowed to stand to precipitate a large quantity of crystals. The

reaction mixture was filtered, and the recovered crystals were washed with water and dried.

47 g. of crystals were obtained. The crystals were light yellow, and had a decomposition point of 190-191 C. Colorless plates having the decomposition point of 194 C. were obtained by recrystalligation from acetone,

4 EXAMPLE 2 4-nitro- 1,2-bis- 3-ethoxycarbonyl-2-thi0ureido benzene (Compound 7) 19.0 g. (0.175 mol.) of ethyl chloroformate were added to 18.0 g. (0.185 mol.) of potassium thiocyanate in ml. oi acetonitrile at room temperature under agitation, and the mixture was heated and kept at a temperature of 35-45 C. on a water bath. 12.3 g. (0.08 mol.) of 4-nitroo-phenylenediamine were dropped into the mixture containing the resulting ethoxycarbonylisothiocyanate, while it was maintained at a temperature of 20-30 C. The reaction mixture was heated on a steam bath for one hour under reflux. Then the reaction mixture was cooled and about 500 ml. of cold water was added thereto.

33.0 g. of crystals were obtained following the procedure of Example 1. Light yellow needles having the decomposition point of 205-206 C. were obtained by recrystallization from acetone.

EXAMPLE 3 1,2-bis-(3-(Z-methoxy)-ethoxycarbonyl-2-thioureido)- benzene (Compound 11) 13.8 g. (0.1 mol.) of Z-methoxyethylchloroformate were added to 10.8 g. (0.11 mol.) of potassium thiocyanate in 80 ml. of acetone at room temperature under agitation, and the mixture was heated and kept at a temperature of 40-45 C. for one hour on a water bath. 4.0 g. (0.037 mol.) of o-phenylenediamine were dropped into the mixture containing the Z-(methoxy)-ethoxycarbonylisothiocyanate produced from said reactants while the mixture was maintained at a temperature of 10-20 C. on an ice water bath. The reaction mixture was heated on a steam bath for one hour under reflux. Then the reaction mixture was cooled to room temperature and about 300 ml. of water was added to the cooled mixture.

14.0 g. of the crystals which formed were recrystallized from acetone to obtain colorless needles having M.P. -171 C.

EXAMPLE 4 1,2-bis-(3-ethylthiocarbonyl-2-thioureido)- benzene (Compound 13) 8.7 g. (0.07 mol.) of S-ethyl chlorothiol tformate were added to 7.8 g. (0.08 mol.) of potassium thiocyanate in 60 ml. of dioxane at room temperature under agitation, and mixture was heated and kept at a temperature of 35 40 for 30 minutes. 3.3 g. (0.03 mol.) of o-phenylenediamrne were dropped into the mixture while it was kept at a temperature of 1020 C. The resulting reaction mixture was kept at room temperature for one hour under agitation. Then dioxane was distilled off from the mixture and about 200 ml. of water were added to the residue. 8 g. of the resulting light yellow crystals were recrystallized from dioxane to obtain colorless prisms having decomposition point of 191l92 C.

EXAMPLE 5 Copper salt of 1,2-bis-(3-ethoxycarbonyl-2-thioureido)- benzene (Compound 28) 59 g. (0.16 mol.) of 1,2-bis(3-ethoxycarbonyl-2-thio uredio)-benzene were added to 13 g. (0.32 mol.) of caustic soda in 700 m1. of water at about 20 C. under agitation. The mixture was agitated for 15 minutes and then filtered. 40 g. (0.16 mol.) of crystallized cupric sulfate (CuSO -5H O) in 300 ml. of water were dropped into the above mixture under agitation. The reaction mixture was agitated at room temperature for one hour, and filtered. The recovered material was washed with water and dried at 50 C.

67.5 g. of powder were obtained. The powder was dark green, and had a decomposition point of 138139 C. 44.5 g. of the dark green powder having the decomposition point of 141-142 C. were obtained by washing the first powder three times with 200 m1. of hot acetone.

EXAMPLE 6 Calcium salt of 1,2-bis-(3-ethoxycarbonyl-2-thioureido)- benzene (Compound 26) 67.5 g. of powder were obtained according to a procedure similar to that of Example 5, except for 26.5 g. (0.18 mol.) of crystallized calcium chloride (CaCl 2H O) in 200 m1. of water instead of g. (0.16 mol.) of crystallized cupric sulfate in 300 ml. of water. The powder was colorless and had a decomposition point of 178-180 C. (d). g. of a colorless powder having a decomposition point of 169-171C. were obtained by washing the first powder three times with 200 ml. of hot acetone.

Some typical compounds of the present invention are listed in Table 1, along with some of their properties.

These typical compounds in Table 1 include merely some of the compounds of the present invention, so that the scope of the present invention is not intended to be limited only to those compounds listed in Table 1.

TABLE 1 Melting point N o. 01 or decomposi- Analysis (percent) for-- comtlon point (d; pound Structural formula Appearance 0. Molecular formula C H N 1 fi C") Colgrless 181. 5-1825 (d) CnHuN|04S s.

NH-c--Nn-c-o-cn, p Sm NH-Cf-NH-(fi-O-OH;

2 S 0 Colorless 195 (d) CuHnN404S| 45.35 5.08 14.90

II It 1 .19 I I paes (45 4) (4.85) (15 NH-O-NH-fi-O-CzH;

3 (I? Colorlgss 205-206((1) (luHnNtOlsg 48.24 o

NH-b-NH-c-o-omcm p w NH-C-NH-O-O-CHKJH,

4 I? P%l9b6t10W 197-198 (d) CuHuN4O Sg 5o 113.185;

NH-o-NH-o-o-cmcmcm a e NH C NH g'-'OCHQCH(CHQ)Q 5 I I? Pale ycelllow -176 (6) CIIHMNOAS, (436.820 55.232 (113.518

0 e. c NH-c-NH-c-o-cm. p w r NH-fi-NH-(fi-O-CzHr 8.......... .....do ..170.5-171.5(d) CuH11ClN4O4Sn 4:15? (4.4.237 c1 NHCNHC-0CaHr NH-(fi-NH-(fi-O-Cnfli 7 S 0 Light yellow 205205.5(d) C||H17N|O Sg 40.20 4.16 16.7]

II II No C N C C,HU plates (40 48) (4 10) (16 87) NHC-NHCOCH ll ll 8 8 S Llghtbrown 206-207((1) CnHuChN|04Sg 38.31 3.71 12.08

I ll cal c1 NH-d-NH-co-clm s as (38 27) (a 67) (12 75) Cl NH-CNH-(l'IJ-OCzHs 9.. Cl Pale brown -181 OuH CltNtOaB: 35.53 3.11 11.91 powder. (35.49) (3.19) (11.83)

Analysis (percent) for- Melting point or decomposition point ((1) No. of 00m- Appearanc C.) Molecular formula pound Structural formula '.'....do.....':.'.: 300 (d) cuHucuNl l l 3 -29 3.08 14. 72

Light yellow 175 (d) CuHuCaNm Sa powder.

C-0 CzHl M 0 m m m w m 1 m m flw mm C m m C C w w CH0. 050 x "W i m m a a Green powder 144 (d) OnfiuCuNflfi:

TABLE 1'Continued Melting point No. of or decomposi- Analysis (percent) forcomtion point ((1) pound Structural formula Appearance (O) Molecular formula C H N 35 N Light green 181 (d) cnnunamoisi 30. 52 2. 47 11.95

powder, (30.36) (2.55) (11.80) NIT-fill 9-00 l I J r H- N WC OCH:

36 N Colorless 150 (d) CuHuCBNACiB: 44.78 3.85 13.21

powder: (44.74) 3.75) (13.04) NH-C COCHzOH=CH2 The compounds listed in Table I possess very superior fungicidal activity compared to known compounds.

In this invention usually a small but effective amount of the compounds is applied to plant surface by spraying, drenching or dusting to protect or control the microbes and diseases. The concentrations of the active ingredients in the fungicidal compositions of this invention vary according to type of formulation, and they are, for example, used in a range of 10-80 weight percent, preferably 40 20-60 weight percent, in wettable powder, 10-70 weight percent, preferably 1050 weight percent, in emulsifiable concentrates, and 05-10 weight percent, preferably 1-5 weight percent in dust formulations. In the above formulation of the composition, auxiliary agents or materials, for example, inert mineral powders such as clay, talc and diatomaceous earth, dispersing agents such as sodium lignin sulfonate and casein, and wetting agents such as alkylarylsulfonate and polyoxyethylene alkylphenol, may be employed according to the type of the formulation for combating fungi and bacteria. Furthermore, the composition may be applied as a mixture with other fungicides, insecticides, acaricides, plant growth regulators and fertilizers.

The non-limiting examples for the fungicidal compositions are illustrated as follows:

EXAMPLE 7 Wettable powder Parts by weight Compound 2 30 Sodium alkylsulfonate 5 Diatomaceous earth Emulsifiable concentrate Parts by weight Compound 23 10 Xylene 45 Cyclohexanone 39 Phenyl polyoxyethylene 6 Dust formulation Parts by weight 2 Compound 5 Talc 98 These were mixed and crushed to fine powder. The dust formulation is usually applied as dusting powder at a rate of 3 to 5 leg. per 10 are.

In the Examples 7-9, it is not intended to limit the emulsifying, wetting or dispersing agents, carriers and solvents to the ones described by way of illustration.

With regard to mammalian toxicity of the typical compound, for example, that of Compound 2 in Table 1 is 15,000 mg./kg. and that of Compound 1 is up to 3,000 mg./kg. as the value of acute order LD-50 for mice.

The superior fungicidal eifects of the novel compounds of this invention are clearly illustrated by the following tests.

TEST 1 Test for control of rice blast disease The compound to be tested was applied as waterdiluted solution of wettable powder prepared according to the method of Example 7. The potted rice plants grown to a 3-leaf stage were sprayed at a rate of 25 cc./pot with solutions of the test materials. One day later, the plants were inoculated with a spore suspension of rice blast fungus, Piricularia oryzae, and held under the condition of incubation (at about 100% relative humidity and 26 C.) in a wet cabinet for 24 hours. Then the plants were moved to a greenhouse bench. Ten days after incubation, number of lesions per pot were examined and evaluation of percent disease control was based upon the percentage of lesions occurring on the untreated check. The results are shown in Table 2.

TABLE 2 Cone. of Average active innumber of Control gredlent, lesions value, Phytovlml. per pot percent toxicity Compound number:

2 600 2. 5 97. 5 None. 1. 99 Do. 3. 96. 5 Do. 0. 0 100 Do. 12. 5 87. 4 Do. 3. 0 97 Do. 16. 0 83. 8 D0. 1. 0 99 D0. 4. 0 96 D0. 0. 5 99. 5 Do. 0 100 Do. 0 100 Do. 0 100 D0. 2. 2 97.8 D0. 0 100 Do. 0 100 Do. 0 100 Do. 4. 0 96.0 Do. 4. 0 96.0 Do.

TEST 2 Test for control of cucumber anthracnose The potted cucumber plants grown to a 3-leaf stage were sprayed at a rate of 50 ml. per 3 plants with waterdiluted solution of the wettable powder prepared by the method of Example 7. One day later, the plants were inoculated with a spore suspension of cucumber anthracnose fungus, Colletotrzchum lagenarium, and held under the condition of incubation (at about 100% relative humidity and 26 C.) in a wet cabinet for 20 hours. Then the plants were moved to a greenhouse bench. Seven days after incubation, average number of lesions per leaf were counted and evaluation of percent disease control was based upon the percentage of lesions occurring on the untreated check. The results are shown in Table 3.

TABLE 3 Cone. of Average Field test for control of Cercospora leaf spot of sugar beets This test was conducted in an attempt to determine the effect of inhibition in development of the Cercospora leaf spot on leaves of sugar beets by the foliage spraying. The field was arranged in a randomized-block design with 4 replicate plots of each treatment consisting of 25 111. per plot. The diluted sprays were applied at the rate of 100 liters per are as a single application after incipient infection was apparent in the leaves. One month after spraying, disease data were taken by counting the infected leaves on 50-450 sugar beets selected at random from each plot and leaf spot severity was rated on a scale ranging from 0 to 5 in which 0=no leaf spot and 5=most of the leaves dead from disease. The results are shown in Table 4.

1 TPTA=Triphenyltin acetate.

16 TEST 4 Test for control of rice sheath blight disease The compounds to be tested were applied as waterdiluted solution of wettable powder prepared by the method of Example 7. The potted rice plants (24-25 plants per single pot) grown to a 5-lcaf stage were sprayed at a rate of 25 cc./pot with solution of the test material. Two days later, the plants were inoculated with mycelia of the rice sheath blight fungus, Corticium sasaki, grown in a culture medium. The plants were transferred to a wet cabinet and held under the condition of incubation (at 100% relative humidity and 2530 C.) for two days. At the end of this time, the plants were moved to a greenhouse bench. Eight days after incubation, number of plants infected were examined in each test pot and the data were recorded as infection rating made on a scale of 0=non infected; 1=up to 5 plants infected/pot; 2=615 plants infected/pot; 3:16 or more plants infected/pot. The results are shown in Table 5.

TABLE 5 Cone. of active ingredient, Infection Phytov/ml. rating toxicity Compound number:

1 500 0. 00 None. 500 0.00 Do. 500 0.00 Do. 500 0.60 Do. 500 0.30 Do. 500 0.30 Do. 500 0.50 Do. 500 1.00 Do. 500 0. 80 D0. 500 0. 50 Do. 500 0. 50 Do. 500 0. 25 Do. 500 0. 25 Do. 500 0.30 Do. 500 0.50 Do. 500 0. 50 Do. 500 0. 10 D0. 500 0.30 D0. 500 0. 10 D0. 500 0.30 Do. 500 0. 50 Do.

We claim: 1. The compound having the formula S O i] ll NH NHC--SR NHCNH(?S$R wherein each of R and R is alkyl having 1 to 12 carbon atoms.

No references cited.

LEWIS GOTIS, Primary Examiner D. R. PHILLIPS, Assistant Examiner US. Cl. X.R. 

